Simple boronic acids are inhibitors of serine proteases. For example, Koehler et al. Biochemistry 10: 2477 (1971) reports that 2-phenylethane boronic acid inhibits chymotrypsin at millimolar levels. The synthesis of boronic acid analogs of N-acyl-.alpha.-amino acids has yielded more effective inhibitors. Ac-boroPhe--OH, R-1-acetamido-2-phenylethane boronic acid, inhibits chymotrypsin with a K.sub.i of 4 .mu.M Matteson et al. J. Am. Chem. Soc. 103: 5241 (1981). More recently, Shenvi, U.S. Pat. No. 4,537,773 (1985) disclosed that boronic acid analogs of .alpha.-amino acids, containing a free amino group, were effective inhibitors of aminopeptidases. Shenvi, U.S. Pat. No. 4,499,082 (1985) discloses that peptides containing an .alpha.-aminoboronic acid with a neutral side chain were more effective inhibitors of serine proteases exceeding inhibitors disclosed earlier by as much as 3 orders of magnitude in potency. The chemistry of .alpha.-aminoboronic acids was further expanded to the synthesis of peptide analogs containing boronic acid with positive charged sidechains, boroLysine, boroArginine, boroOrnithine, and isothiouronium analogs (EPA 0 293 881, Dec. 7, 1988). This series of compounds have provided highly effective inhibitors of thrombin and other trypsin-like enzymes. The boroArginine analogs specifically designed as thrombin inhibitors are highly effective in the inhibition of blood coagulation both in vitro and in vivo. In the present invention, this group of compounds is extended to aliphatic amidino and formamidino, to aromatic amidino and guanidino, to cyano and halogen, and to other neutral substituted aromatic boronic acid analogs.
It should be noted that additional boronic acids have been disclosed. Metternich (EP 0471651) have described peptides containing boroArginine and boroLysine which contain at least one unnatural amino acid residue. Elgendy et al. Tetrahedron Lett., 33, 4209-4212 (1992) have described peptides containing .alpha.-aminoboronic acids with aliphatic neutral sidechains which are thrombin inhibitors. Kakkar in (WO 92/07869) has claimed peptide thrombin inhibitors of the general structure, X-Aa.sub.1 -Aa.sub.2 -NH-CH(Y)-Z where Aa.sub.1 and Aa.sub.2 are unnatural amino acid residues. Z is --CN, --COR, --B(R.sup.2)(R.sup.3), -P(O)(R)(R), and Y is --[CH.sub.2 ].sub.n -Q or --CH.sub.2 --Ar-Q where Q=H, amino, amidino, imidazole, guanidino or isothioureido and n=1-5 and where R.sub.2 and R.sub.3 are the same or different and are selected from the group consisting of OH, OR.sup.6, and NR.sup.6 R.sup.7, or R.sup.2 and R.sup.3 taken together represent the residue of a diol. This specialized group of compounds where Z is -B(R.sup.2)(R.sup.3) fall within the scope of our present application. It should be noted that this is a narrow subset of Kakkar et al. However, rather specialized chemical transformations are required to prepare these compounds and Kakkar et al. does not make an enabling disclosure.